Browsing by Author "Larance, Mark"

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    Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress
    Byrne, Frances L.; Olzomer, Ellen M.; Marriott, Gabriella R.; Quek, Lake-Ee; Katen, Alice; Su, Jacky; Nelson, Marin E.; Hart-Smith, Gene; Larance, Mark; Sebesfi, Veronica F.; Cuff, Jeff; Martyn, Gabriella E.; Childress, Elizabeth; Alexopoulos, Stephanie J.; Poon, Ivan K.; Faux, Maree C.; Burgess, Antony W.; Reid, Glen; McCarroll, Joshua A.; Santos, Webster L.; Quinlan, Kate G. R.; Turner, Nigel; Fazakerley, Daniel J.; Kumar, Naresh; Hoehn, Kyle L. (2020-01)
    A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD(+) ratios exclusively in cancer cells, and induces necrosis. BH10 targets mitochondrial redox defence as evidenced by increased mitochondrial peroxiredoxin 3 oxidation and decreased mitochondrial aconitase activity, without changes in markers of cytosolic or nuclear damage. Over-expression of mitochondria-targeted catalase protects cells from BH10-mediated toxicity, while the thioredoxin reductase inhibitor auranofin synergistically enhances BH10-induced peroxiredoxin 3 oxidation and cytotoxicity. Overall, BH10 represents a 1,4-Naphthoquinone with an improved cancer-selective cytotoxicity profile via its mitochondrial specificity.